Tectorigenin alleviates diabetic lung injury by restoring gut microbiota and metabolic homeostasis

Given the heightened susceptibility to lung injury in diabetes mellitus and the critical role of gut dysbiosis in metabolic diseases, this study aimed to investigate whether Tectorigenin (TG) could alleviate diabetic lung injury by restoring gut microbial and metabolic homeostasis. Using a streptozotocin (STZ)-induced diabetic mouse model, we comprehensively evaluated TG's effects on lung histopathology, systemic inflammation (TNF-a, IL-1b, IL-6), the gut microbiome (16S rRNA sequencing), and fecal metabolites (untargeted metabolomics) to elucidate its mechanisms. Significantly, TG treatment markedly reduced lung histopathological damage and inflammatory infiltration, concomitant with decreased pro-inflammatory cytokine levels and restored expression of lung tight junction proteins (ZO-1/Occludin). Crucially, TG effectively corrected gut dysbiosis by restoring the Firmicutes/Bacteroidetes ratio, enriching beneficial bacteria (e.g., g_Lactobacillus, g_Limosilactobacillus), and suppressing pathogenic bacteria (e.g., Enterobacteriaceae, Helicobacter). Furthermore, metabolomic analysis revealed that TG restored major disrupted microbial metabolic pathways (energy, amino acid, and lipid metabolism), suppressed pro-inflammatory signaling (e.g., reduced PGE2, 15-HETE), and consequently inhibited pulmonary oxidative stress (reduced ROS, elevated Nrf2/GPX1), macrophage M1 polarization (lower CD86/CD206 ratio), mitochondrial dysfunction (elevated PGC-1a, SIRT-1), and ferroptosis. Integrated network analysis established significant correlations linking gut microbial abundance (notably g__Anaerostipes), metabolite profiles, and lung injury markers, clarifying the intrinsic gut-lung axis connection in diabetes. Collectively, our findings demonstrate that Tectorigenin effectively mitigates diabetic lung injury primarily by targeting the gut microbiota-metabolism-lung axis to maintain metabolic homeostasis. This study presents a novel potential intervention strategy for preventing and treating diabetic pulmonary complications.